Formoterol is a long-acting β2-adrenoceptor agonist and has a long duration of action of up to 12 hours. Chemically it is termed as N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]-formamide. The structure of formoterol is as shown below.

The asterisks indicate that formoterol has two chiral centers in the molecule, each of which can exist in two possible configurations. This gives rise to four diastereomers which have the following configurations: (R,R), (S,S), (S,R) and (R,S).
(R,R) and (S,S) are mirror images of each other and are therefore enantiomers. Similarly (S,R) and (R,S) form other enantiomeric pair.
The commercially-available formoterol is a 50:50 mixture of the (R,R)- and (S,S)-enantiomers. (R,R)-formoterol is an extremely potent full agonist at the β2-adrenoceptor and is responsible for bronchodilation and has anti-inflammatory properties. On the other hand (S,S)-enantiomer, has no bronchodilatory activity and is proinflammatory.
Murase et al. [Chem. Pharm. Bull., 26(4)1123-1129(1978)] synthesized all four isomers of formoterol and examined for β-stimulant activity. In the process, racemic formoterol was subjected to optical resolution with tartaric acid.
In another attempt by Trofast et al. [Chirality, 3:443-450(1991)], racemic 4-benzyloxy-3-nitrostyrene oxide was coupled with optically pure N—[(R)-1-phenylethyl]-2-(4-methoxyphenyl)-(R)1-methylethylamine to give diastereomeric mixtures of intermediates, which were separated by column chromatography and converted to the optically pure formoterol.
In yet another attempt, racemic formoterol was subjected to separation by using a chiral compound [International publication WO 1995/018094].
WO 1998/21175 discloses a process for preparing optically pure formoterol using optically pure intermediates (R)—N-benzyl-2-(4-methoxyphenyl)-1-methylethyl amine and (R)-4-benzyloxy-3-formamidostyrene oxide.
Preparation of optically pure formoterol is also disclosed in IE 20000138 and GB 2380996.
Increasing use and therapeutic benefit and use through newer drug delivery, Metered Dose Inhaler (MDI) necessitates further research to develop new improved processes for the synthesis of formoterol which are suitable for industrial scale up with improved impurity profile.